Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
  • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

• This invention is in the field of clinical neurology and relates specifically to a class of therapeutically useful compounds, compositions and methods for treatment of central nervous system (CNS) dysfunctions, neurotoxic damage, or neurodegenerative diseases.
• CNS central nervous system
• these compounds are particularly useful for treating neurotoxic injury which follows periods of hypoxia, anoxia or ischemia associated with stroke, cardiac arrest or perinatal asphyxia.
• These compounds are also useful as antipsychotics and anticonvulsants.
• brain tissue is particularly sensitive to deprivation of oxygen or energy. Permanent damage to neurons can occur during brief periods of hypoxia, anoxia or ischemia.
• Neurotoxic injury is known to be caused or accelerated by certain excitetory amino acids (EAA) found naturally in the central nervous system (CNS).
• EAA excitetory amino acids
• CNS central nervous system
• Glutamate (Glu) is an endogenous amino acid which has been characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathological conditions which accompany stroke and cardiac arrest. Normal glutamate concentrations are maintained within brain tissue by energy-consuming transport systems.
• hypoglycemia Under low energy conditions which occur during conditions of hypoglycemia, hypoxia or ischemia, cells can release glutamate. Under such low energy conditions the cell is not able to take glutamate back into the cell. Initial glutamate release stimulates further release of glutamate which results in an extracellular glutamate accumulation and a cascade of neurotoxic injury.
• Glutamate is characterized as a broad spectrum agonist having activity at three neuronal excitatory amino acid receptor sites. These receptor sites are named after the amino acids which selectively excite them, namely: Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) and quisqualate (QUIS).
• agents which selectively block or antagonize the action of glutamate at the EAA synaptic receptors of central neurons can prevent neurotoxic injury associated with hypoxia, anoxia, or ischemia caused by stroke, cardiac arrest or perinatal asphyxia.
• Certain nitrogen-containing cyclohetero cycloalkylaminoaryl compounds are known for pharmaceutical purposes.
• U.S. Pat. No. 4,2204,003 to Szmuszkovicz describes N-(2-aminocyclopentyl)-N-alkanoylanilides as antidepressant agents.
• CNS disorders and diseases such as cerebral ischemia, psychotic disorders and convulsions, as well as prevention of neurotoxic damage and neurodegenerative diseases, may be accomplished by administration of a therapeutically-effective amount of a compound of the formula: ##STR2## wherein each of R, R 1 , R 4 , R 5 , R 6 and R 7 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein each of R 2 , R 3 and R 10 through R 15 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl,
• a preferred family of compounds of Formula I consists of those compounds wherein each of R, R 1 , R 4 , R 5 , R 6 and R 7 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkanoyl, alkenyl and alkynyl; wherein each of R 2 , R 3 and R 10 through R 15 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alken
• R 16 may be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, alkanoyl, aralkanoyl and aroyl; wherein each of R 17 through R 20 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, haloalkyl, hydroxyalkyl, carboxyalkyl and alkanoyl; wherein A is selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio and
• a more preferred family of compounds within Formula I consists of those compounds wherein each of R, R 1 , R 4 , R 5 , R 6 and R 7 is independently selected from hydrido, loweralkyl, cycloalkyl of three to about eight carbon atoms, phenylloweralkyl, phenyl, loweralkoxyloweralkyl, haloloweralkyl; hydroxyloweralkyl, carboxy, carboxyloweralkyl, loweralkanyl, loweralkenyl, loweralkynyl; wherein R 2 , R 3 and R 10 through R 15 is independently selected from hydrido, hydroxy, loweralkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenylloweralkyl, phenyl, loweralkoxy, phenoxy, phenylloweralkoxy, loweralkoxyloweralkyl, halo
• R 16 may be selected from hydrido, loweralkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl, phenylloweralkyl, heteroaryl, loweralkanoyl, phenylalkanoyl, benzoyl, aminoloweralkyl, monoloweralkyl-aminoloweralkyl and diloweralkylamino-loweralkyl; wherein each of R 17 and R 18 is independently selected from hydrido, hydroxy, loweralkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyloweralkyl, phenyl, loweralkoxyloweralkyl, haloloweralkyl, hydroxyloweralkyl,
• a more highly preferred family of compounds of Formula I consists of those-compounds wherein each of R, R 1 , R 4 , R 5 , R 6 and R 7 is independently selected from hydrido, loweralkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, loweralkoxyloweralkyl, haloloweralkyl, hydroxyloweralkyl, loweralkanoyl, loweralkenyl, and loweralkynyl; wherein R 2 , R 3 and R 10 through R 15 is independently selected from hydrido, hydroxy, loweralkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, loweralkoxy, phenoxy, benzyloxy, loweralkoxyloweralkyl, halo
• R 16 may be selected from hydrido, loweralkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, phenyl and benzyl; wherein each of R 17 through R 20 is independently selected from hydrido, loweralkyl, cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms, benzyl, phenyl, loweralkoxyloweralkyl, hydroxyloweralkyl and halo; wherein A is selected from phenyl, naphthyl, benzo b!thienyl, thienyl, phenoxy, benzyloxy, naphthyloxy, thiophenoxy, phenylamino, benzylamino, naphthylamino,
• a family of compounds of particular interest within Formula I are compounds embraced by Formula II: ##STR7## wherein each of R, R 1 , R 4 , R 5 , R 6 and R 7 is independently selected from hydrido, loweralkyl, benzyl and haloloweralkyl; wherein each of R 2 , R 3 and R 10 through R 13 is independently selected from hydrido, hydroxy, loweralkyl, benzyl, phenoxy, benzyloxy and haloloweralkyl; wherein each of R 8 and R 9 is independently selected from hydrido, loweralkyl, benzyl and haloloweralkyl; wherein m is an integer of from two to four; wherein A is selected from phenyl, naphthyl, benzothienyl, benzofuranyl and thienyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydrido, hydroxy,
• a more preferred family of compounds within Formula II consists of compounds wherein each of R, R 1 , R 4 , R 5 , R 6 and R 7 is independently selected from hydrido, methyl, ethyl, propyl, benzyl, and haloloweralkyl, wherein each of R 2 , R 3 and R 10 through R 13 is independently selected from hydrido, hydroxy, methyl, ethyl, propyl, benzyl, phenoxy, benzyloxy and haloloweralkyl; wherein each of R 8 and R 9 is independently selected from hydrido, methyl, ethyl, propyl, benzyl and haloloweralkyl; wherein m is an integer of from two or three; wherein A is phenyl or naphthyl; wherein any of the foregoing A groups can be further substituted with one or more substituents independently selected from hydroxy, methyl, ethyl, propyl
• hydro denotes a single hydrogen atom (H) which may be attached, for example, to an oxygen atom to form hydroxyl group.
• alkyl is used, either alone or within other terms such as “haloalkyl” and “hydroxyalkyl”
• alkyl embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about ten carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about five carbon atoms.
• cycloalkyl embraces cyclic radicals having three to about six carbon atoms, such as cyclopropyl and cyclobutyl.
• haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo groups, preferably selected from bromo, chloro and fluoro.
• haloalkyl preferably selected from bromo, chloro and fluoro.
• haloalkyl preferably selected from bromo, chloro and fluoro.
• a monohaloalkyl group for example, may have either a bromo, a chloro, or a fluoro atom within the group.
• Dihaloalkyl and polyhaloalkyl groups may be substituted with two or more of the same halo groups, or may have a combination of different halo groups.
• a dihaloalkyl group may have two bromo atoms, such as a dibromomethyl group, or two chloro atoms, such as a dichloromethyl group, or one bromo atom and one chloro atom, such as a bromochloromethyl group.
• An example of a polyhaloalkyl is a trifluoromethyl group.
• alkylol and hydroxyalkyl embrace linear or branched alkyl groups having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl groups.
• alkenyl embraces linear or branched radicals having two to about twenty carbon atoms, preferably two to about ten carbon atoms, and containing at least one carbon-carbon double bond.
• alkynyl embraces linear or branched radicals having two to about twenty carbon atoms, preferably two to about ten carbon atoms, and containing at least one carbon-carbon triple bond.
• cycloalkenyl and cycloalkynyl embrace cyclic radicals having three to about ten ring carbon atoms including, respectively, one or more double or triple bonds involving adjacent ring carbons.
• alkoxy and “alkoxyalkyl” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy group.
• the "alkoxy” or “alkoxyalkyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or haloalkoxyalkyl groups.
• heteroaryl embraces aromatic ring systems containing one or two hetero atoms selected from oxygen, nitrogen and sulfur in a ring system having five or six ring members, examples of which are thienyl, furanyl, pyridinyl, thiazolyl, pyrimidyl and isoxazolyl including benz-fused systems such as benzothienyl, 2-quinolinyl and the like.
• alkylene chain describes a chain of two to six methylene (--CH 2 --) groups which may form a cyclic structure with or without a hetero atom in the cyclic structure.
• alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, methyl-butyl, dimethylbutyl and neopentyl.
• Typical alkenyl and alkynyl groups may have one unsaturated bond, such as an allyl group, or may have a plurality of unsaturated bonds, with such plurality of bonds either adjacent, such as allene-type structures, or in conjugation, or separated by several saturated carbons.
• compositions of Formulas I-II include the tautomeric forms of the described compounds, isomeric forms including enantiomers and diastereoisomers, and the pharmaceutically-acceptable salts thereof.
• pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. Since the compounds of Formulas I-II contain basic nitrogen atoms, such salts are typically acid addition salts.
• pharmaceutical phrase "pharmaceutically-acceptable salts” is not intended to embrace quaternary ammonium salts. The nature of the salt is not critical, provided that it is pharmaceutically acceptable, and acids which may be employed to form salts are, of course, well known to those skilled in this art.
• acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and phosphoric acid, and such organic acids as maleic acid, succinic acid and citric acid.
• Other pharmaceutically acceptable salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium and magnesium, or with organic bases, such as dicyclohexylamine. All of these salts may be prepared by conventional means by reacting, for example, the appropriate acid or base with the corresponding compound of Formulas I-II in a suitable solvent (e.g. methanol).
• a process for preparing the compounds of the invention starts with an oxo derivative of a bridged azabicycloalkane of general structure 1 where R, R 1 , R 8 through R 13 , and n have the value assigned previously.
• An examples of a compound within the general structure 1 is 3-quinuclidone.
• the salt, e.g. hydrochloride, of 1 is converted to the corresponding oxime with hydroxylamine hydrochloride and sodium acetate in a suitable solvent, e.g. ethanol.
• the reaction can be conducted over a wide temperature range such as from room temperature to reflux. ##STR9## wherein R, R 1 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and n are as defined previously.
• compounds of the general formula 2 are converted to the corresponding 3-keto-1,4-diazabicycloalkane derivative 3.
• This conversion is achieved by reacting a compound of formula 2 with an acid, such as trifluoroacetic acid.
• an acid such as trifluoroacetic acid.
• R, R 1 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and n are as defined previously.
• compounds of general structure 3 are treated with a reducing agent such as lithium aluminum hydride in a suitable solvent such as tetrahydrofuran.
• the resulting product 4 is a diazabicycloalkane.
• diazabicycloalkanes of general structure 4 are converted to amides of general structure 6 where A, R 2 , and R 3 have the value assigned previously and L 1 is a good leaving group such as chloro, bromo, acyloxy, or "activated" hydroxy.
• the conversion can be best achieved by mixing the reagents neat or in an aprotic solvent such as tetrahydrofuran, methylene chloride, or ether in the presence of a base such as triethylamine.
• the reaction can be run in the absence or presence of an activating agent such as dicyclohexylcarbodiimide or phosphorus oxychloride, depending on the leaving group of choice.
• the temperature of the reaction can vary from 0° to reflux of the reaction mixture. ##STR12## wherein A, R, R 1 , R 2 , R 3 , R 8 through R 13 and n are as defined previously.
• amides of general structure 6 are converted to amines of general structure 7 by employing reducing agents such as lithium aluminum hydride, aluminum hydride, sodium borohydride, sodium cyanoborohydride, or .Other reducing agents familiar to those skilled in the art.
• This reduction can be accomplished in either protic or aprotic solvents, depending on the reducing agent of choice, and at temperatures ranging from room temperature to reflux of the reaction mixture.
• amines of general structure, 9 can be prepared according to the following generic procedure: ##STR13## wherein A, R 1 through R 5 , R 8 through R 13 and m and n are as defined previously; and wherein L 2 is a good leaving group such as halogen, tosylate, mesylate, or brosylate.
• the compounds can be combined in a variety of solvents such as toluene, xylenes, dimethylformamide, hexamethylphosphoramide, or ethanol.
• solvents such as toluene, xylenes, dimethylformamide, hexamethylphosphoramide, or ethanol.
• the temperature of the reaction can vary from room temperature to reflux of the reaction mixture.
• Example 1 The title compound of Example 1 (10 g, 71.4 mmol) in a 250 mL rb flask was treated with CF 3 COOH (30 mL) with stirring. The solution became hot and then became viscous as it cooled to room temperature. TLC (1:9:90 concentrated aqueous ammonia --MeOH--CHCl 3 1:9:90) indicated the reaction to be 95% complete after 10 minutes at room temperature. After 1 hour, reaction was complete. The reaction mixture was poured into a solution of K 2 CO 3 (67 g) in water (200 mL) and extracted with CHCl 3 (4 ⁇ 200 mL).
• Example 2 The title compound of Example 2 (1.70 g, 12.1 mmol) was added portionwise at room temperature to a stirred solution of AIH 3 (60 mL of a 1.0M solution, 60 mmol). The solution became warm. Stirring was continued for a further 20 minutes and the reaction mixture was poured into cold (5° C.) 30% aqueous KOH solution (100 mL) and the aqueous mixture was extracted with CHCl 3 (200 mL). The organic extract was dried (Na 2 SO 4 ) and evaporated to give the title compound in quantitative yield: mp 250° C.
• AIH 3 60 mL of a 1.0M solution, 60 mmol
• Example 3 HCl salt of the (1.5 g, 7.56 mmol) was coupled with 3,4-dichlorophenylacetic acid (2.32 g, 11.3 mmol) in the presence of 1,3-dicyclohexylcarbodiimide (3.11 g, 15.1 mmol, 2.0 eq) and triethylamine (2.29 g, 3.0 eq) in CH 2 C 12 (50 ml). After stirring overnight at room temperature, the reaction mixture was filtered and the filter-cake was washed with a little (25 ml) of ether. The combination filtrate and washings were washed with 10% citric acid (100 ml) and the organic layer was discarded.
• citric acid layer was washed with ether (2 ⁇ 50 ml) and then basified (to pH 9.5) with excess concentrated aqueous NH 3 solution. Extraction with CH 2 Cl 2 (50 ml) drying (Na 2 SO 4 ) and evaporation of the solvent afforded the product as an oil which was converted to the oxalate salt (0.64 g, 21%) mp 180°-182° C.
• Example 4 The title compound of Example 4 (0.39 g, 1.24 mmol) was reduced with 1.0M AIH 3 in THF as described in Example 3 to give the fumarate of the title compound (0.30 g, 45%): mp 167°-168° C.
• Example 5 The compound of Example 5 was tested for its ability to displace 3 H!(+)-pentazocine from guinea pig brain membranes de Costa et al, FEBS Lett., 251, 53-58, 1989! to determine the relative potency of the compounds interacting with the sigma receptor. Receptor binding assays were performed using the crude synaptosomal (P 2 ) membrane fraction of guinea pig brain.
• Crude P 2 membrane fractions were prepared from frozen (-80° C.) guinea pig brains (Pel-Freeze, Rogers, Ak.), minus cerebella. After removal of cerebella, brains were allowed to thaw slowly on ice and placed in ice-cold 10 mM Tris-HCl, pH 7.4, containing 320 mM sucrose (Tris-sucrose buffer). Brains were then homogenized in a Potter-Elvehjem homogenizer by 10 strokes of a motor driven Teflon pestle in a volume of 10 mL/g tissue wet weight. The homogenate was centrifuged at 1000 g for 10 min at 4° C., and the supernatants were saved.
• the pellets were resuspended by vortexing in 2mL/g ice-cold Tris-sucrose and centrifuged again at 1000 g for 10 min. The combined 1000 g supernatant was centrifuged at 31000 g for 15 min at 4° C. The pellets were resuspended by vortexing in 3 mL/gm of 10 mM Tris-HCl, pH 7.4, and the suspension was allowed to incubate at 25° C. for 15 min. Following centrifugation at 31000 g for 15 min, the pellets were resuspended by gentle Potter-Elvehjem homogenization to a final volume of 1.53 mL/g in 10 mM Tris-HCl, pH 7.4.
• rat brain crude P 2 membranes male Sprague-Dawley rats (150-200 g, Charles River, Boston, Mass.) were sacrificed by decapitation. Brains (minus cerebella) were then treated as described above. &
• Each compound was initially screened at concentrations of 10, 100, and 1000 nM in order to obtain an estimate of sigma binding affinity and to determine the appropriate concentration range to use in 12-point competition curves. For most compounds in the study, a concentration range of 0.0005-100 nM was appropriate. A range of 0.005-1000 nM or 0.05-10,000 nM was used for the less potent compounds. Twelve concentrations of unlabeled ligand were incubated with 3 nM 3 H!(+)-pentazocine as described previously de Costa et al, FEBS Lett., 251, 53-58, 1989!. The CDATA iterative curve-fitting program (EMF Software, Inc., Baltimore, Md.) was used to determine IC 50 values.
• EMF Software, Inc., Baltimore, Md. was used to determine IC 50 values.
• compositions comprising one or more compounds of Formula I in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier” materials) and, if desired, other active ingredients.
• carrier non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants
• the compounds of the present invention may be administered by any suitable route, preferably in the form a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
• Therapeutically effective doses of the compounds of the present invention required to prevent or arrest the progress of the medical condition are readily ascertained by one of ordinary skill in the art.
• the compounds and composition may, for example, be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
• the pharmaceutical compositions may be in the form of, for example, a tablet, capsule, suspension or liquid.
• the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. These may with advantage contain an amount of active ingredient from about 1 to 250 mg, preferably from about 25 to 150 mg.
• a suitable daily dose for a mammal may vary widely depending on the condition of the patient and other factors. However, a dose of from about 0.1 to 3000 mg/kg body weight, particularly from about 1 to 100 mg/kg body weight, may be appropriate.
• the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
• a suitable daily dose is from about 0.1 to 100 mg/kg body weight injected per day in multiple doses depending on the disease being treated. A preferred daily dose would be from about 1 to 30 mg/kg body weight.
• Compounds indicated for prophylactic therapy will preferably be administered in a daily dose generally in a range from about 0.1 mg to about 100 mg per kilogram of body weight per day.
• a more preferred dosage will be a range from about 1 mg to about 100 mg per kilogram of body weight.
• Most preferred is a dosage in a range from about 1 to about 50 mg per kilogram of body weight per day.
• a suitable dose can be administered, in multiple sub-doses per day.
• a dose or sub-dose may contain from about 1 mg to about 100 mg of active compound per unit dosage form.
• a more preferred dosage will contain from about 2 mg to about 50 mg of active compound per unit dosage form.
• Most preferred is a dosage form containing from about 3 mg to about 25 mg of active compound per unit dose.
• the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination.
• the dosage regimen actually employed may vary widely and therefore may deviate from the preferred dosage regimen set forth above.
• the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
• the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
• Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
• Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
• the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, aqueous sodium chloride, and/or various buffers.
• Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

Abstract

Description

              TABLE II                                                    
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               Ki ( 3H! (+) -Pent)                                        
Test Compound  nM                                                         
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Compound of Ex. 5                                                         
               125                                                        
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• 1994
  • 1994-11-21 US US08/344,304 patent/US5679673A/en not_active Expired - Fee Related

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